Long-term use of methylprednisolone, as with all corticosteroids, can be associated with hyperglycemia, decreased resistance to infection, swelling of face, weight gain, congestive cardiac insufficiency, fluid and sodium retention, edema, hypertension, increased eye pressure, glaucoma, osteoporosis, and psychosis, especially when used at high doses.[6][7] The most serious side effect occurs after the adrenal glands cease natural production of cortisol, which methylprednisolone will replace. Abrupt cessation of the drug after this occurs can result in a condition known as Addisonian crisis, which can be fatal. To prevent this, the drug is usually prescribed with a tapering dose, including a predosed "dose pack" detailing a specific number of tablets to take at designated times over a several-day period. Pharmacists sometimes advise that this drug may cause sleeplessness and "down" moods.

Individuals on methylprednisolone therapy should assiduously avoid exposure to measles and chicken pox, as contracting these viral infections while on high-dose corticosteroids can result in a potentially fatal viral course. Any accidental exposure to these viral infections by individuals uncertain of their immunity to chicken pox or measles should be reported immediately as prophylactic immunoglobulin therapy may be administered. Additionally, the administration of live, attenuated vaccines is contraindicated for individuals taking immunosuppressive doses of methylprednisolone. The exception to this rule is patients receiving complete corticosteroid replacement therapy, e.g., for Addison's disease, who may follow standard immunization protocols.

Unbound glucocorticoids cross cell membranes and bind with high affinity to specific cytoplasmic receptors, modifying transcription and protein synthesis. By this mechanism, glucocorticoids can inhibit leukocyte infiltration at the site of inflammation, interfere with mediators of inflammatory response, and suppress humoral immune responses. The anti-inflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.